Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned (based on read-across)
Justification for type of information:
A read-across approach is applied between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3) for the human health endpoints due to the structural similarity of the two reaction products (Scenario 6 in ECHA’s RAAF document), both resulting from the same starting materials (only the ratio is different), and through the same manufacturing process.
Commercial MEA Polyborate products are commonly formulated at either 1:1 or 1:3 mole ratios of MEA to boric acid, or sometimes at ratios in between. All compositions in this range contain equilibrium mixtures of the exact same chemical species, but with somewhat different population distributions.
The existing physico-chemical, toxicological, environmental fate and ecotoxicological data already showed good correlation with no significant differences between the two ratios.

The results of the newly commissioned, additional anchoring studies (water solubility, vapour pressure and octanol-water coefficient, Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assays, acute toxicity studies via dermal route and oral route) showed good correlation between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3), and therefore further supported our category hypothesis.

However, no toxicokinetic (absorption, metabolism, distribution, elimination) data is available for MEA-Polyborate. Available data is primarily physico-chemical properties that influence the absorption and distribution of the substance in the body. This data provides limited information indicating a read-across approach between the reaction products of MEA Polyborate 1:1 and 1:3 for the human health endpoints is likely justified for repeated dose studies including developmental toxicity studies. However, since no data is available on the metabolism of MEA-Polyborate, additional data is needed to justify read across for repeated dose studies. In this case data from dose range finding studies for the proposed developmental toxicity and 90-day toxicity studies will provide the requisite information if read-across is justified.

Category: MEA Polyborates

TESTING PROPOSAL ON VERTEBRATE ANIMALS
Extended one-generation reproductive toxicity study (EOGRTS, Annex X, Section 8.7.3.; Test method: EU B.56, OECD TG 443) in rats or rabbits, oral route

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Reaction products of monoethanolamine and boric acid (1:3)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies and non-GLP studies:
There is no existing reliable (GLP or non-GLP) data on the reproductive toxicity in rats.
This is a standard information requirement for which data must be provided. The information on this endpoint is not available for the registered substance, but needs to be present in the registration dossier to meet the information requirements.

- (Q)SAR
Due to the presence of inorganics and the complex chemistry, the substance falls outside of the applicability domain of the globally recognized (Q)SAR models. Therefore, no (Q)SAR modelling has been carried out on Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3)

- In vitro methods
The application of in vitro methods is not relevant to the assessment of the effects of MEA Polyborates 1:1/1:3 in an extended one-generation reproductive toxicity study in rats (via the oral route) given the biological complexity of the endpoint.

- Grouping and read-across
It is proposed that the Expended One-Generation Reproductive Toxicity Study (EOGRTS, OECD 443) to be conducted in MEA Polyborate 1:3. The result will be used to fill the reproductive screening endpoint of MEA Polyborate 1:1.
Category name: MEA Polyborates

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Section 8.7.1 of Annex VIII of REACH states that a Screening for reproductive/developmental toxicity study (one species) (OECD 421 or 422) shall be conducted.

Testing of the Extended OneGeneration Reproductive Toxicity of rats (via the oral route) on MEA Polyborates 1:3 will address the requirement of Section 8.7.1 of Annex VIII of REACH.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed
It is proposed that an Extended one-generation reproductive toxicity study (EOGRTS, Annex X, Section 8.7.3.; Test method: EU B.56, OECD TG 443) in rats or rabbits, oral route will be conducted on MEA Polyborates 1:3 according to OECD Guideline for testing of chemicals 443.
Further reproductive and developmental studies may potentially be proposed based on the result of developmental studies (OECD TG414) and the EOGRTS study proposed on MEA Polyborates 1:3.

No further cohorts can be identified at this time as there is no existing data on this substance for the 90-day or development endpoints.

We propose a tiered testing strategy: where additional tests are required under Annexes IX and X; it is proposed that these tests be conducted sequentially where relevant (e.g. to address the same endpoint), for the reasons outlined below. As part of this tiered strategy the developmental study (EU B.31/OECD TG414) will be conducted prior the 90-day study (OECD TG 408), whith the EGRTS OECD TG 443 study conducted last.
i. Results from one test may render a subsequent test unnecessary, as appropriate classification and labelling information and risk management measures may be able to be derived from these without other tests.
ii. Results from one test may help as range finders for subsequent tests and/or may help in refining the protocol.
iii. On the grounds of animal welfare (as outlined in REACH recitals 13, 33, 37, 40, 49, 50, 64 and especially 47), and Article 13(1) and (2)), in vivo tests on vertebrate animals are to be minimised and avoided where possible. Utilisation of a tiered testing strategy, in which additional tests are potentially avoided dependent on the results of preceding tests, is desirable and consistent with the aims and objectives of REACH.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Version / remarks:
Study not yet conducted. An Extended One-Generation study is proposed on MEA Polyborate 1:1 which wil be used for read-across.
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS :

It is proposed that an Extended one-generation reproductive toxicity study (EOGRTS, Annex X, Section 8.7.3.; Test method: EU B.56, OECD TG 443) in rats or rabbits, oral route will be conducted on MEA Polyborates 1:3 according to OECD Guideline for testing of chemicals 443.
Further reproductive and developmental studies may potentially be proposed based on the result of developmental studies (OECD TG414) and the EOGRTS study proposed on MEA Polyborates 1:3.

No further cohorts can be identified at this time as there is no existing data on this substance for the 90-day or development endpoints.

We propose a tiered testing strategy: where additional tests are required under Annexes IX and X; it is proposed that these tests be conducted sequentially where relevant (e.g. to address the same endpoint), for the reasons outlined below. As part of this tiered strategy the developmental study (EU B.31/OECD TG414) will be conducted prior the 90-day study (OECD TG 408), whith the EGRTS OECD TG 443 study conducted last.
i. Results from one test may render a subsequent test unnecessary, as appropriate classification and labelling information and risk management measures may be able to be derived from these without other tests.
ii. Results from one test may help as range finders for subsequent tests and/or may help in refining the protocol.
iii. On the grounds of animal welfare (as outlined in REACH recitals 13, 33, 37, 40, 49, 50, 64 and especially 47), and Article 13(1) and (2)), in vivo tests on vertebrate animals are to be minimised and avoided where possible. Utilisation of a tiered testing strategy, in which additional tests are potentially avoided dependent on the results of preceding tests, is desirable and consistent with the aims and objectives of REACH.

Test material

1
Reference substance name:
Reaction products of monoethanolamine and boric acid (1:3)
EC Number:
701-024-0
Cas Number:
-
Molecular formula:
C2H7NO.xBH3O3
IUPAC Name:
Reaction products of monoethanolamine and boric acid (1:3)
Test material form:
liquid
Remarks:
clear colourless
Details on test material:
UVCB
At room temperature protected from light
31 March 2018 (expiry date)

Results and discussion

Applicant's summary and conclusion